Mefloquine is the main antimalarial used for treatment of falciparum malaria patients at the malaria clinics in Thailand. However, the cure rate with mefloquine alone has declined seriously in recent years. The efficacy and tolerability of a sequential treatment of artesunate followed by mefloquine was therefore compared with those of mefloquine alone, in a randomized therapeutic trial involving 125 patients with acute uncomplicated falciparum malaria. Sixty-three patients received mefloquine alone (750 mg given immediately, followed by 500 mg 6 h later) and 62 each received 800 mg artesunate over 2 days (200 mg every 12 h) followed 6 h later by a single, 750-mg dose of mefloquine. All patients were admitted to the hospital in Bangkok for 28 days to exclude re-infection. Most patients (107) completed the study; 18 left the hospital prior to completion of follow-up for reasons unrelated to their treatment. Cure rates for the two groups were 74% (42/57) for mefloquine alone and 92% (46/50) for artesunate followed by mefloquine. The mean parasite clearance time was significantly shorter (P < 0.001) in the group treated with the sequential combination than in the group treated with mefloquine alone, but the mean fever clearance times were not significantly different (P = 0.26). Most patients responded well to the treatment regimens and none suffered from serious toxic adverse reactions. Only four patients who were treated with mefloquine alone had parasitaemia persisting to day 7 (RII), thus requiring alternative follow-up treatment.(ABSTRACT TRUNCATED AT 250 WORDS)